Structure-function defects of the TWINKLE linker region in progressive external ophthalmoplegia
Structure-function defects of the TWINKLE linker region in progressive external ophthalmoplegia
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DOI：
10.1016/j.jmb.2008.01.035
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发表时间：
2008-03-28
影响因子：
5.6
通讯作者：
Falkenberg, Maria
中科院分区：
文献类型：
--
作者：
Korhonen, Jenny A.;Pande, Vineet;Falkenberg, Maria
TWINKLE是哺乳动物细胞中线粒体DNA（mtDNA）复制叉上的解旋酶。编码TWINKLE的PEO 1基因突变会导致常染色体显性进行性眼外肌麻痹（AdPEO），这是一种与线粒体DNA缺失相关的疾病。在这里，我们的特点是七个不同的AdPEO引起的TWINKLE连接区的突变，我们确定了不同的分子表型。对于一些突变，蛋白质六聚化和DNA解旋酶活性被完全消除，而另一些则显示出更微妙的影响。为了更好地理解这些不同的表型，我们基于噬菌体T7基因4蛋白的三维结构构建了TWINKLE的分子模型。结构模型解释了分子表型，并预测了其他AdPEO引起的突变的功能后果。我们的研究结果提供了一个分子平台，为进一步研究细胞和动物为基础的模型系统，并表明，噬菌体T7 DNA复制机制的知识可能是关键的理解突变的mtDNA复制装置的分子和表型的后果。(C)2008年由Elsevier Ltd.出版
TWINKLE is the helicase at the mitochondrial DNA (mtDNA) replication fork in mammalian cells. Mutations in the PEO1 gene, which encodes TWINKLE, cause autosomal dominant progressive external ophthalmoplegia (AdPEO), a disorder associated with deletions in mtDNA. Here, we characterized seven different AdPEO-causing mutations in the linker region of TWINKLE and we identified distinct molecular phenotypes. For some mutations, protein hexamerization and DNA helicase activity are completely abolished whereas others display more subtle effects. To better, understand these distinct phenotypes, we constructed a molecular model of TWINKLE based on the three-dimensional structure of the bacteriophage T7 gene 4 protein. The structural model explains the molecular phenotypes and also predicts the functional consequences of other AdPEO-causing mutations. Our findings provide a molecular platform for further studies in cell- and animal-based model systems and demonstrate that knowledge of the bacteriophage T7 DNA replication machinery may be key to understanding the molecular and phenotypic consequences of mutations in the mtDNA replication apparatus. (C) 2008 Published by Elsevier Ltd.